UMEM Educational Pearls - Toxicology

If benzodiazepines and supportive care fail to improve agitation and correct vital signs, several case reports indicate the successful use of cyproheptadine, an antihistamine with nonspecific antagonist effects at 5-HT_1A and 5-HT_2A receptors.

Cyproheptadine is available in 4 mg tablets or 2 mg/5 mL syrup. When administered as an antidote for serotonin syndrome, an initial dose of 8-12 mg is recommended, followed by 2 mg every two hours until clinical response is seen. Cyproheptadine is only available in an oral form, but it may be crushed and given through a nasogastric tube.

Cyproheptadine may lead to sedation, but this effect is consistent with the goals of management. It may also produce transient hypotension due to the reversal of serotonin-mediated increases in vascular tone. Such hypotension usually responds to IV fluids. Cyproheptadine is rated category B for safety in pregnancy by the FDA.

Ingestion of caustics can lead to immediate burns to mouth, esophagus, stomach as well as possible perforation. Months and years later, further complications are esophageal stenosis and increased incidence of esophageal carcinoma. The main benefit to EGD is to determine extent of injury within the esophagus. The lesions are graded much like a burn: 

Grade I: Mild burn, no risk for esophageal stenosis

Grade II: Moderate, if circumferential, patient is at risk for esophageal stenosis

Grade II: Eschar present, high risk of perforation as well as esophagel stenosis

You can make a case that all intentional-suicidal ingestions of caustics should undergo EGD since there should be some injury if ingestion truly occurred or at the least a higher probability. The difficult case is the pediatric unintentional ingestion. Utilizing clinical exam and history will assist with that determination - there is a little research to guide this decision (next pearl)

The attached picture is the post-mortem of a caustic injury showing grade II linear lesions in esophagus with eschar distally and in stomach (Grade III).

A patient arrives via EMS agitated with VS: P 140, BP 155/100, R 18, T 101F. There is an admitted drug exposure and you examine his eyes which are dilated. You shine the light in the eyes - if the pupil reacts, would that be consistent with anticholinergic or sympathomimetic toxidrome?

Answer: Anticholinergic exposure paralyzes pupillary constrictor muscles and causes dilated pupils that do not react to light. Think about when you go to the eye doctor's office. They put homoatropine in your eyes so that when they look with the slit lamp they can see the retina without interference from pupillary constriction. Sympathomimetic exposure like cocaine activates pupillary dilator muscles, the constrictors are still intact and will give a reflexive constriction to light.  This patient has reactive pupils and by the mere fact is in Baltimore probability dictates a sympathomimetic exposure like cocaine.

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Valproic Acid (Depakote) is a drug that uniquely has the ability to raise serum ammonia concentrations. It is able to do this without raising liver er enzymes and it can occur in overdose or at therapeutic levels. Do not think of this in the context of hepatic encephalopathy. This a metabolic derangement caused by VPA.

• Any patient with somnolence, lethargy, decreased responsiveness - order a serum ammonia level as well as Valproic acid level
• If the serum ammonia is elevated in conjunction with altered mental status consider a trial of carnitine
• L-carnitine is a safe drug that is used in nutritional supplementation. VPA and other anticonvulsants cause carnitine deficiency
• Most effective dose is unknown but from a recent review: IV 100 mg/kg once, followed by infusions of 50 mg/kg (to a maximum of 3 g per dose) every 8 hours until patient improves, ammonia decreases

Show References

  Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic Acid overdose: a   systematic review of published cases. Ann Pharmacother. 2010  Jul-Aug;44(7-8):1287-93. Epub 2010 Jun 29.

In a patient with toxin-induced bradycardia and hypotension, here is a quick differential to help identify the responsible substance:

• Beta blockers
• Calcium channel blockers
• Cholinergics
• Clonidine (and other alpha-2 agonists)
• Digoxin (and other cardiac glycosides)
• Opioids
• Sedative hypnotics (such as benzodiazepines and barbiturates)

Less commonly seen causes include: magnesium, propafenone, and plant toxins (aconitine, andromedotoxin, veratrine).

In the state of Maryland, the most common venomous snake is the copperhead. Though not as dangerous as the rattlesnake, it can still cause loss of function of limb and mortality in the pediatric patient.

Treatment has involved the use of CroFab (Protherics, Atlanta). This ovine derived monovalent immunoglobolin is actually made against the following snakes:

• Eastern diamondback rattlesnake
• Western diamondback rattlesnake
• Mojave rattlsnake
• Cottonmouth (Water moccasin)

Though efficacy has been shown with these snakes, we are hoping for cross-reactivity when we treat copperheads. There are case series and case reports (1) that have shown anectdotal improvement. We are still awaiting a real randomized controlled trial - may never happen.

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Physostigmine has been used extensively in the fields of anesthesiology and emergency medicine.  The only use of physostigmine with sound scientific support is for the management of patients with an anticholinergic syndrome, particularly those without cardiovascular compromise who have an agitated delirium.  In this population, physostigmine has an excellent risk-to-benefit profile.

• Try benzodiazepines first.  They last longer and may diminish the need for physostigmine.
• Obtain ECG.  If there are signs of sodium channel blockade (QRS prolongation), do not use physostigmine.
• Administer 1-2 mg via slow IV push/infusion over at least 5 minutes.
• Have atropine available at the bedside.
• Effects last about 1 hour.

There are a several classes of medications that can kill a toddler with a single dose. Toddlers are particularly susceptible due to their low weights and propensity to place everything in their mouths.

1. Calcium channel blockers
2. Camphor-containing rubs
3. Opioids/opiates
4. Oil of wintergreen/ aspirin
5. Cyclic antidepressants
6. Topical blood pressure patches (clonidine)
7. Eye drops and nasal sprays (oxymetazoline)
8. Sulfonylureas
9. Antimalarial drugs (cloroquine)

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Scombroid is caused by ingestion of preformed histamine on skin of fish.

• Naturally occurring histidine on scaly fish converted to histamine by surface bacteria - often fish left out too long, refrigeration will prevent the conversion.
• Bacteria responsible are Morganelli morganii and K. pneumoniae
• Fish: tuna, mahi mahi, amberjack, bonito, mackerel, albacore
• Fish usually appears normal though meat may tast peppery
• Patient presents minutes/hrs flushed, urticaria, HA, N/V
• Self-limited and improve within hrs even without treatment
• Antihistamines and rarley epinephrine will be needed

We are all familiar with the classic ECG abnormalities caused by the sodium channel blocking properties of tricyclic antidepressants (QRS interval widening, R wave in aVR, S wave in I and aVL, and rightward deviation in terminal 40 msec of QRS). Here are some other medications that also block cardiac sodium channels in a similar manner:

• Cocaine
• Diphenhydramine
• Cyclobenzaprine (Flexeril)
• Carbamazepine (Tegretol)
• Phenothiazines
• Propoxyphene
• Class 1A antidysrhythmics (quinidine, procainamide, disopyramide)
• Class 1C antidysrhythmics (encainide, flecainide, propafenone, moricizine)
• Amantadine

It is likely that you will be asked questions about the huge recall by McNeil..

It stems from complaints received of black particles found in the pediatric liquid formulation, which are manufactured at one facility in Fort Washington, PA.  The FDA inspected the plant and found inadequate quality standard testing and facilities. Either there were potential bacteria in one of the raw products (which did not make it to the final product), or the final concentrations were stronger than specified.

McNeil recalled forty-three formulations of pediatric liquid tylenol, zyrtec, motrin and benadryl. Generic versions are unaffected.

Complete recall information:

www.mcneilproductrecall.com

For more information and links:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm210442.htm

Several drugs and compounds may be radiopaque on an abdominal radiograph. This may be helpful in an overdose to determine ingestion or amount ingested. Attached is a pic a patient that ingested potassium sustained release tables.

The mneumonic CHIPES will help you remember which are:

C - Calcium Carbonate, chloral hydrate

H - Heavy metal - like Mercury, lead

I - Iron and Iodine

P - Phenothiazines (compound that has S(C₆H₄)₂NH in it), drugs that include: antipsychotics like chlorpromazine (thorazine) and antiemetics like prochlorperazine (compazine)

E - Enteric coated pills

S - Solvents [halogenated ones like chloroform] and Sustained Release preparations [Lithobid and K-Dur]

Attachments

• 1004150936_KCl_patient_1.JPG (182 Kb)

Many drugs/toxins cause nystagmus, particularly in overdose.  Vertical, horizontal, or rotary nystagmus may be noted.

The most common drug/toxin overdoses that cause nystagmus are the following:

• Anticonvulsants (phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate)
• Ethanol
• Lithium
• Dextromethorphan
• Phencyclidine (PCP)
• Ketamine
• Lysergic acid diethylamide (LSD)

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When you draw a urine toxicology screen it can mislead more often than help you. Here is a quick list of the test followed by some medications that cause false positives - when in doubt, call your lab to find out specifics since results will vary lab to lab:

TCA - diphenhydramine, carbamazepine, cyclobenzaprine (side note: TCA screen should never be used to determine TCA toxicity, your ECG and physical exam should be enough to determine if the patient is toxic from TCA

Cocaine - the most accurate test on the screen, positive for up to 5 days

PCP - dextromethorphan and ketamine can turn it positive

Amphetamines - pseudoephedrine, ephedrine, phenylephrine and many other OTC cough decongestants can as well, the worst screening test with the largest number of false positives

According to the Food Allergy and Anaphylaxis Network, the eight most common food allergies, which account for 90% of the food allergies in the U.S., are: dairy, soy, wheat, shellfish, fish, peanut, tree nut, and egg.

Several medications are formulated with these ingredients and should be avoided in patients with reported allergies.

• Propofol is a lipid emulsion that contains egg.  Avoid in patient with hypersensitivity to eggs, egg products, soybeans, or soy products.
• Ipratropium ± albuterol (Atrovent, Combvient®) inhalers may contain soy lecithin.  This can cause allergic reactions in patients with allergy to soy lecithin or related food products (e.g., soybean and peanut).  Nebulizer solutions (e.g., Duoneb®) seem to be free from this issue.
• Progesterone (Prometrium®) capsules contain peanut oil.

When a child is reported to be exposed to a rat poison it is commonly a long acting coumarin like brodifacoum. The rat usually eats the poison then during its traumatic little life will cause its own death by jumping and squeezing through a crack. When a human is exposed, this is the typical sequence of events:

1. Exposure (and when you usually see them in the ED)
2. 24-72 hrs later you will actually see an INR rise if actually ingested

Treatment is the same as for coumadin, vitamin K. However, do not start empirically since the patient will be committed to high doses of vitamin K for several months. Let the patient prove they have been poisoned which means they will require recheck of their INR 2-3 days later though they can be sent home with specific warning signs of anticoagulation.

With all of the post-transplant patients we see in the ED, a refresher on the toxicities associated with the most common immunosuppressant medications is warranted.

Cyclosporine (Sandimmune^® and Neoral^®/Gengraf^®) and tacrolimus (Prograf^®) are both calcineurin inhibitors that inhibit activation and proliferation of T-lymphocytes and IL-2.

-          Major concerns: Nephrotoxicity, drug interactions (CYP3A4)

-          Adverse Effects:

o       Electrolyte abnormalities: ­K+, ¯Mg+, ­glucose

o       CNS: HA, tremor (statistically higher with tacrolimus)

o       CV: HTN, ­ lipids (increased with cyclosporine)

o       End organ: hepatotoxicity, nephrotoxicity

o       Cosmetic (cyclosporine specific): hirsutism, gingival hyperplasia, acne

Sirolimus/Rapamycin (Rapamune^®) is an M-tor inhibitor that inhibits T-lymphocyte activation and proliferation.

-          Major concerns: Drug interactions (CYP3A4)

-          Adverse Effects:

o       Delayed wound healing

o       Leucopenia, thrombocytopenia

o       Hypercholesterolemia